An intensive research effort in the field of cephalosporin antibiotics has produced a number of clinically significant cephalosporin compounds. One of the more recent developments in this area has been the discovery of cephem compounds directly substituted with halogen at the C-3 position. A number of 3-halo-3-cephems have been described by Chauvette in U.S. Pat. Nos. 3,925,372, 4,064,343 and 3,962,227. These potent antibiotic compounds are prepared by halogenation of the corresponding 3-hydroxy-3-cephems. The halogenation of 3-hydroxy-3-cephems to provide 3-chloro and 3-bromo-3-cephems has typically been carried out by reacting the 3-hydroxy-3-cephem compounds with brominating or chlorinating agents including phosgene, oxalyl chloride, thionyl chloride, thionyl bromide and phosphorous halides such as phosphorous trichloride and phosphorus tribromide, usually in the presence of dimethylformamide.
This invention is directed to a process for preparing 3-halo-3-cephems and related thiazoline azetidinone vinyl halides utilizing novel halogenating reagents.
More particularly this invention is directed to a process for halogenating 7-acylamino 3-hydroxy 3-cephem compounds with novel halogenating compounds of the general formula ##STR1## wherein Z is hydrogen, halo, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy, and X is Cl or Br, which halogenating compounds are the kinetically controlled products of the reaction of equivalent amounts of a triaryl phosphite of the formula ##STR2## and chlorine or bromine in a substantially anhydrous inert organic solvent. The products of the present process are 7-acylamino-3-chloro-3-cephem compounds or, depending on the reaction conditions selected, the corresponding 3-chloro-3-cephem imino halides which are easily converted to the related 7-amino-3-chloro-3-cephem derivatives. The 3-halo-3-cephems are known antibiotics or are intermediates thereto.
In another embodiment of this invention novel thiazolineazetidinone vinyl halide compounds of the formula ##STR3## are prepared from the corresponding enols of the formula ##STR4## utilizing the aforedescribed novel halogenating reagents. The thiazolineazetidinone vinyl halides (R=H) have been found to exhibit antibacterial activity.